The health-related quality of life in patients with post-COVID-19 after hospitalization: a systematic review

ABSTRACT Symptoms in post-COVID-19 patients who require hospitalization can persist for months, significantly affecting their health-related quality of life (HRQoL). Thus, the present study aimed to discuss the main findings regarding HRQoL in post-COVID-19 patients who required hospitalization. An electronic search was performed in the MEDLINE, EMBASE, CINAHL, Web of Science, LILACS, and Scopus databases, without date and language restrictions, until July 2021. Twenty-four articles were included in the analysis. It seems that HRQoL partially improved soon after hospital discharge, although the negative impact on HRQoL may persist for months. The physical and mental aspects are affected because patients report pain, discomfort, anxiety, and depression. The HRQoL of COVID-19 infected patients was worse than that of uninfected patients. Additionally, HRQoL seemed worse in patients admitted to the intensive care unit than in those who remained in the ward. Improvements in HRQoL after hospital discharge are independent of imaging improvement, and there seems to be no association between HRQoL after hospital discharge and disease severity on hospital admission. Many factors have been identified as determinants of HRQoL, with women and advanced age being the most related to worse HRQOL, followed by the duration of invasive mechanical ventilation and the need for intensive care. Other factors included the presence and number of comorbidities, lower forced vital capacity, high body mass index, smoking history, undergraduate education, and unemployment. In conclusion, these findings may aid in clinical management and should be considered in the aftercare of patients.


INTRODUCTION
COVID-19 is an acute respiratory infection caused by the potentially serious SARS-CoV-2, with high transmissibility and global distribution 1 . SARS-CoV-2 is a beta-coronavirus that was discovered in the city of Wuhan, China, in December 2019. Coronaviruses are a large family of viruses common to different species of animals 2 .
COVID-19 has generated great concern in the population due to its ability to cause serious conditions in a large proportion of infected patients 3,4 . Approximately 20% of hospitalized patients develop severe complications, including respiratory failure, acute respiratory distress syndrome (ARDS), shock, delirium, and multiple organ dysfunction 5,6 . In addition, critical patients greatly require therapies such as mechanical ventilation, which usually requires prolonged intensive care unit stays and post-COVID-19 rehabilitation 7,8 . Thus, such factors can decrease health-related quality of life (HRQoL) due to the physical, cognitive, and mental impairments of individuals with critical illnesses 9,10 .
HRQoL provides a complete assessment of the impact of a disease on patients' daily lives 11 . A structured review 12 was recently conducted to verify the scores from different HRQoL questionnaires in post-COVID-19 patients. However, the general aspects of HRQoL after hospital discharge still require discussion. Even with no need for hospitalization, many patients may have a worse HRQoL than non-infected individuals 13 . However, due to the prolonged length of hospital stay, the need for invasive mechanical ventilation, pain, and fear of death, the investigation of HRQoL among hospitalized patients is of paramount importance. Therefore, the present study proposes systematically discussing the main findings of HRQoL in patients post-COVID-19 that required hospitalization. Establishing the general aspects of the HRQoL of these patients and identifying their determinants can help in the management of patients after hospital discharge.

Study design
This systematic review aimed to discuss the main findings on the HRQoL of post-COVID-19 patients after hospitalization. The study was edited following the PRISMA checklist 14 and Cochrane recommendations 15 . The protocol was prospectively registered in the open science framework (https://osf.io/k9pu6/).

Search strategy and study selection
Search strategies were conducted using the Medical Literature Analysis and Retrieval System Online (MEDLINE), EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, Latin American and Caribbean Health Sciences Literature (LILACS), and Scopus databases. There were no language restrictions from their inception until July 2021. The following strategy was be used for the PubMed search -[("COVID-19" OR "SARS-CoV-2" OR "post-acute COVID-19 syndrome" OR "SARS-CoV-2 variants" OR "COVID-19 post-intensive care syndrome" OR "COVID-19 stress syndrome") AND ("Quality of Life" OR "Life Quality" OR "Health-Related Quality Of Life" OR "Health Related Quality Of Life" OR "HRQOL")], being modified for each database. After the searches, the retrieved references were exported to an Endnote® file, removing duplicates. Two independent reviewers checked for full texts using titles and abstracts. Studies that met our eligibility criteria were included in the review, and discrepancies between reviewers were resolved by a third reviewer.

Eligibility criteria
This review included published observational studies, such as cross-sections, cohort, or control case studies, which assessed HRQoL in post-COVID-19 patients, after hospitalization, from both sexes, and at any age. Eligibility criteria included studies a) that evaluated patients post-COVID-19 after hospitalization; b) and assessed HRQoL. The exclusion criteria were articles in duplicate, studies that did not report the questionnaire used, papers that aimed to verify the improvement of HRQoL after rehabilitation, and those that did not match the objective of this review. In addition, studies that assessed only the questionnaire's psychometric properties were also excluded, as it is not yet possible to establish a gold standard.

Quality assessment
Two independent reviewers (EABF and WTS) assessed the methodological quality of the included studies using the Newcastle-Ottawa Scale 16 . This scale assigns a maximum of ten points for the lowest risk of bias and zero for the highest risk of bias. Newcastle-Ottawa scores the risk of study bias in three domains: 1) selection of study groups (four points), 2) group comparability (two points), and 3) verification of exposure and results (three points) for case-control and cohort studies, respectively.
For cross-sectional studies, Newcastle-Ottawa Scale has a maximum score of ten stars, divided into the topics "selection," "comparability," and "results" 17 . To assess the risk of bias, studies that scored in all domains (selection, comparability, and outcome) were classified as high quality 18 . Those who did not score in at least one of the domains were classified as low-quality. All studies found in the electronic search, regardless of the methodological quality, were included in the review.

Outcome and data analysis
The extracted data included the year of publication, sample characteristics, HRQoL questionnaire used, and results. We did not perform a meta-analysis, and the results were presented as descriptive data. The corresponding author was contacted in the presence of any missing data.

RESULTS OF THE ELECTRONIC SEARCH
We retrieved 4757 titles, of which 1513 were duplicates and excluded. The remaining 3244 studies were screened, and 57 references were selected for inclusion in the study. Of these, 24 met our inclusion criteria. Figure 1 outlines the flow of the review papers. The SF-36/Rand-36 is a generic questionnaire that encompasses 36 items grouped into eight domains: physical functioning, physical, bodily pain, general health, social functioning, roleemotional, vitality, and mental health. The total score ranges from 0 (lowest HRQL) to 100 (highest HRQL), and the higher the score, the better the patient's HRQoL 19,20 . The SF-12 is a generic HRQoL assessment instrument composed of a 12-item subset of SF-36. It assesses the same eight HRQoL domains of SF-36 21,22 . The 5-level EQ-5D (EQ-5D-5L) has two parts: the EQ-5D descriptive system and the EQ visual analog scale (EQ-VAS). The descriptive system had five dimensions: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. In addition, the questionnaire allowed five levels of response: no problems, slight problems, moderate problems, severe problems, and extreme problems. Higher values indicate better health. The EQ-VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labeled from "The best health you can imagine" to "The worst health you can imagine" 23 . Another version, EQ-5D-3L, is similar to the EQ-5D-5L. However, it has three response levels: no problems, some problems, and extreme problems.
The WHOQOL-Bref is a general instrument comprising 26 questions. The first question referred to the general HRQoL, the second to self-satisfaction, and the other 24 to the physical, psychological, social relations, and environment domains 24 . The higher the score, the better the HRQoL of the patient.
The 15D is a generalist instrument that covers 15 dimensions: breathing, mental function, speech (communication), vision, mobility, usual activities, vitality, hearing, eating, elimination, sleeping, distress, discomfort and symptoms, sexual activity, and depression. It is a questionnaire designed to be administered within 10 minutes 25 . Higher scores indicate worse HRQoL. Saint George's Respiratory Questionnaire (SGRQ) is one of the leading HRQoL assessment questionnaires specific to respiratory diseases. It comprises items divided into three sessions: symptoms, activity, and impacts (which cover a range of aspects concerned with social and psychological functioning). The score for each session and the total score can be calculated 26 . The higher the score, the worse is the HRQoL.
EQ-5D-5L 6 months after hospitalization Seventy patients reported a negative change in any of the dimensions of the EQ 5D-5L when compared to before COVID-19.

Study Sample characteristics
Objective related to HRQoL Instrument Follow-up Outcomes Methodological quality Overall quality and 32.6% of the patients, respectively 32 . Therefore, the HRQoL of post-COVID-19 patients may remain worse during the months following discharge.
Temperoni et al. 38 verified the HRQoL of 64 patients aged less than 50 years post-COVID-19 and showed no difference between hospitalized and non-hospitalized patients in any SF-36 domains after one month of hospital discharge. In a small sample (n=39), Monti et al. 30 reported that, after two months of intensive care unit discharge, a majority of patients showed no difficulty in walking, self-care, and usual activities in EQ-5D-5L, and only eight patients reported anxiety or moderate depression. Using the same questionnaire, with a similar follow-up period (six weeks after hospital discharge) and a small sample, Daher et al. 27 showed that patients reported only slight to moderate abnormalities with mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. In contrast, three other studies found different results with larger samples and using the same questionnaire. Navarro et al. 31 found that after mild to moderate COVID-19 infection, a severe decrease in HRQoL was observed in 56% of patients, mainly in usual activities and anxiety/depression. Another study 35 found that 32% of patients had anxiety/depression and 38% reported worsening HRQoL three months after hospital discharge (p<0.001), especially in pain/discomfort and anxiety/depression. Finally, Walle-Hansen 36 showed that 66% of patients (n=106) reported a negative change in any of the dimensions of the EQ 5D-5L when compared to the time before COVID-19. These changes are related to difficulties in performing activities of daily living, reduced mobility, and pain or discomfort. In summary, according to studies with larger samples, pain/discomfort (physical aspects) and anxiety/depression (mental aspects) were the most compromised domains in post-COVID-19 patients after hospitalization.
More studies in post-COVID-19 patients are needed, but patient-reported pain may have multiple causes. Pain may be a consequence of a viral infection in the peripheral neuromuscular or central nervous system, or may occur as a result of invasive mechanical ventilation, or may be secondary to associated syndromes, such as Guillain-Barré syndrome 39 . Joint pain, chest pain, headache, and myalgia are among the most cited symptoms by patients 40,41 .
Regarding the mental aspects, according to Mendéz et al. 29 , anxiety, depression, and post-traumatic stress disorder were detected in 29.6%, 26.8%, and 25.1% of patients, respectively. In addition, 39.1% of patients had psychiatric impairments. Another study 33 demonstrated that HRQoL was impaired in 31% of patients, and symptoms of depression, anxiety, and post-traumatic stress disorders were detected in 11%, 25%, and 11% of the patients, respectively. Maheshwari et al. 28 also found that fear of reinfection by hospital exposure and social stigma was experienced by 51% and 49% of plasma donors, respectively. These results suggest that not only the physical aspects but also the mental health, anxiety, depression, and fear of post-COVID-19 patients should be addressed in post-discharge follow-up.
Thus, the results suggest that (1) some improvements in HRQoL are detectable a few days after hospital discharge, (2) poor HRQoL may persist for months after discharge, and (3) impairments in both physical (pain and discomfort) and mental (anxiety and depression) aspects are present and must be addressed in patient management.

COMPARISON BETWEEN HRQOL BETWEEN PATIENTS WITH POST-COVID-19 AND UNINFECTED POPULATION
Six included studies 32,42-46 compared the HRQoL between post-Covid patients and uninfected individuals ( Table 2). The questionnaires used were SF-36, 15D, SF-12, and SGRQ. The mean quality score was 7 (range, [6][7][8]. Five were classified as high-quality, while only one was of low quality.     Two studies compared the HRQoL evaluated by SF-36 between patients post-COVID-19 and data about the general Chinese population. One study 42 demonstrated that the HRQoL of post-COVID-19 patients was reduced in all SF-36 domains, except for physical functioning, one month after hospital discharge. Another one 32 reported that the HRQoL of post-COVID-19 patients was worse in many domains, except for general health, after three months of hospital discharge. In the Dutch population, it was demonstrated that the HRQoL evaluated by SF-36 was reduced in many domains after six weeks of hospital discharge, except for bodily pain 46 .
In Italian and Finnish populations, Gamberini et al. 43 demonstrated that the HRQoL assessed using the 15D instrument was also worse when compared to data from the general population. In a small sample, another study 44 demonstrated that HRQoL was significantly reduced in patients with post-COVID-19-related pneumonia when compared to the general population three months after hospital admission.
Finally, Raman et al. 45 selected 58 patients diagnosed with COVID-19 and assessed HRQoL using SF-36 from two to three months after symptom onset and compared the HRQoL with a control group (n=30 uninfected individuals matched for age, sex, body mass index, and risk factors). The authors demonstrated that HRQoL was worse in all the SF-36 domains.
Briefly, all included data were consistent, with good methodological quality, and showed that the HRQoL of post-COVID-19 patients was worse than that of the uninfected group even after hospital discharge. These findings can be explained by factors such as pulmonary impairment 47 , fatigue, muscular pain 37 , and anxiety 31 .

THE HRQOL OF POST-COVID-19 PATIENTS ADMITTED AND NOT ADMITTED TO THE INTENSIVE CARE UNIT
Five studies 38,41,[48][49][50][51] compared HRQoL between patients admitted and those not admitted to the intensive care unit ( Table 3). The questionnaires used were WHOQOL-Bref and EQ-5D-5L. The mean quality score was 6.4 (ranging, 5-7), were classified as high-quality.
Halpin et al. 49 were the first to verify the HRQoL of patients with post-COVID-19 admitted to the ward and in the intensive care unit. They demonstrated that in a short period, there was a significant improvement in HRQoL assessed by EQ-5D-5L in both groups. Using the same questionnaire, Garrigues et al. 41 demonstrated no difference between groups of patients admitted to the ward and intensive care unit after 10 days after hospital discharge. Using the WHOQoL-Bref, Albu et al. 48 also found no difference in HRQoL between patients with persistent symptoms admitted (n=16) and those not admitted (n=14) to the intensive care unit after three months of hospital discharge. Based on these results, it seems that being in the intensive care unit or adopting more invasive treatment strategies does not influence the HRQoL of patients after COVID-19. However, prolonged mechanical ventilation is associated with a more extended intensive care unit and hospital stays 52 , as well as significant and lasting physical and psychological dysfunction in critically ill survivors 53 .
Corroborating this sentence, two other studies demonstrated differences in HRQoL between patients admitted and not admitted to the intensive care unit, both using the EQ-5D-5L questionnaire. Huang et al. 50 described, in a larger sample, that patients who needed supplemental oxygen, high-flow nasal cannula, non-invasive mechanical ventilation, or invasive mechanical ventilation had worse scores in the mobility, pain or discomfort, and anxiety or depression domains when compared to those without supplemental oxygen. Finally, Lerum et al. 51 reported that the HRQoL of patients admitted to the intensive care unit was worse after prolonged hospital discharge (greater than three months) in the usual activities domain than that of patients admitted only to regular wards.
The results are conflicting, despite the high methodological quality. However, four studies, using regression analysis, demonstrated that the need for intensive care unit 35,54 or duration of invasive mechanical ventilation 43,55 were independent determinants of the HRQoL of post-COVID-19 patients. Thus, it seems that patients admitted to the intensive care unit have a worse HRQoL than those not admitted, even after hospital discharge.

FACTORS ASSOCIATED AND DETERMINANTS OF HRQOL IN PATIENTS WITH POST-COVID-19
Identifying factors associated with the HRQoL of post-Covid patients is required to assist in patient stratification and guide clinical management. Nine included studies ( Table 4) verified the factors associated with HRQoL in post-COVID-19 32,35,[42][43][44]48,[54][55][56] , with a mean score of 6.6 (ranging, [5][6][7][8]. Seven of these were classified as high quality. The questionnaires used were WHOQOL-Bref, SF-12, EQ-5D-5L, SF-36, 15D, SGRQ, RAND-36, and EQ-5D-3L. One study 44 reported no difference in SF-12 and SGRQ scores between groups who improved their chest computed tomography scan (n=31) and those who did not (n=8) after three months    of hospital admission. Thus, there seems to be no association between imaging improvements and HRQoL after the follow-up period. Anastasio et al. 56 also reported that there was no significant correlation between the physical or mental component summary of the SF-12 and lung function, development of pneumonia, acute respiratory distress syndrome, invasive mechanical ventilation, partial oxygen saturation/fraction of inspired oxygen ratio, or pneumonia severity index four months after COVID-19 diagnosis (n=379). Another study 43 showed that clinical severity at admission was poorly correlated with HRQoL three months after intensive care unit discharge. According to these results, HRQOL was not associated with clinical measures. This can be explained by the fact that COVID-19 encompasses biological, psychological, and social factors, such as stigma and discrimination between various groups, as previously demonstrated 57 . However, many studies have reported fatigue and mental health issues in post-COVID-19 patients. Albu et al. 48 showed a significant correlation between poor HRQoL, fatigue, and anxiety/depression.
Another six studies 32,35,42,43,54,55 verified the independent determinants of HRQoL of patients in the post-COVID-19 period. The main determinants of the poor physical component of HRQoL were obesity and overweight 42 , female sex, older age (≥60 years), and the presence of physical symptoms after hospital discharge 32 . On the other hand, the independent determinants of poor mental components were women 42 and the presence of physical symptoms after hospital discharge 32 . Thus, physical symptoms after hospital discharge and female sex were determinants of poor HRQoL in both physical and mental components in post-COVID-19 patients.
In fact, in all six studies, female sex and old age were determinants of poor HRQoL in the post-COVID-19 period. It has been previously demonstrated that men have higher rates of disease severity and case-fatality 58 , but women suffer more from long-term symptoms than men 55 . Additionally, old age contributes to poor physical and mental health recovery status 32 .
Other determinants of poor HRQoL in post-COVID-19 patients include clinical subtype of the disease 42 54 , and heart failure diagnosis 54 . Taken together, the recognition of these factors can help identify patients with worse HRQoL and should be considered when managing patients to improve their HRQoL.

FINAL CONSIDERATIONS
In summary, the present study suggests that, in post-COVID-19 patients who required hospitalization, (1) HRQoL partially improved soon after hospital discharge; (2) HRQoL impairment persists for months, both in physical and mental aspects; (3) the HRQoL in patients who were infected is worse when compared to uninfected individuals, even months after hospital discharge; (4) the HRQoL seems to be worse in patients admitted to the intensive care unit when compared to those who remained in the ward; (5) improvement in the HRQoL of patients after hospital discharge is independent of imaging improvement; (6) there is no evidence to support the association between HRQoL after hospital discharge and disease severity on hospital admission; (7) women and old age are the most established determinants of HRQoL; and (8) other clinical, demographic, and lifestyle factors may be associated with the HRQoL of patients and should be used to develop tailored strategies in their clinical management.